Renal failure is a major cause of mortality in diabetics. It has been estimated that each year approximately 3200 diabetics die of renal disease. Unfortunately, despite numerous studies, the pathogenesis of diabetic glomerulonephropathy is incompletely understood. It is therefore not surprising that apart from the controversial role of careful control of blood sugar there are currently no means for preventing or retarding the development of diabetic glomerulonephropathy. The purpose of the proposed research is to study the role of certain factors potentially amenable to modification, on the development of diabetic glomerulonephropathy. In particular we will examine the role of hypertension, renal blood flow and the route of insulin administration. Firstly, animals with either genetic or drug induced diabetes will be made hypertensive and the effect of hypertension and the treatment thereof on the nephropathy of diabetes will be examined. Secondly, in normotensive diabetic animals renal blood flow will be reduced with antihypertensive agents in order to reduce exposure of the glomeruli to the intravascular factors that may produce the nephropathy. Thirdly, in other diabetic animals the effect of subcutaneous versus intraperitoneal insulin will be examined. Intraperitoneally injected insulin should expose the liver to higher concentrations of hormone than occurs by subcutaneous injection, simulating the situation in normals with functioning pancreatic beta cells. By providing the liver with higher concentrations of insulin the biochemical disturbances of diabetes may be better controlled and development of nephropathy perhaps retarded. The use of animal models of genetic and experimental diabetes may help in elucidating the role of genetic and biochemical factors in the development of diabetic microvascular disease.